Role of CHD7 in Neural Development and Maintenance.

Abstract

Normal tissue development and maintenance require precise timing and correct localization of gene expression. Several lines of evidence indicate that the chromodomain (CHD) family of proteins are critical regulators of chromatin remodeling and gene expression. In humans, haploinsufficiency for CHD7 causes CHARGE syndrome, a multiple anomaly condition characterized by ocular coloboma, heart defects, choanal atresia, retarded growth and development, genital hypoplasia and ear abnormalities. Many patients with CHARGE display Kallmann-like features which include olfactory and endocrine dysfunction. Clinical evidence indicates that mutations in CHD7 lead to pleiotropic developmental defects; however, the mechanisms underlying these defects have not yet been determined. In order to study the role of CHD7, we generated mice carrying a Chd7Gt allele derived from Chd7 deficient, gene trapped lacZ reporter embryonic stem cells and mice with a conditional Chd7 null allele, Chd7flox. Homozygous Chd7 null mice are embryonic lethal by E11. Chd7Gt/+ mice exhibit features similar to human CHARGE phenotypes, including postnatal growth delay, vestibular dysfunction, and olfactory defects which include olfactory bulb hypoplasia and severely impaired olfaction. Our data indicate that olfactory dysfunction may primarily result from defects in neural stem cell proliferation and reduced olfactory sensory neurons in the olfactory epithelium. However, defects in neural stem cell proliferation in the subventricular zone of the forebrain may also contribute to olfactory bulb defects which occur in both humans and mice with Chd7 deficiency. Additionally, decreased cellular proliferation in the E10.5 olfactory placode causes reduced GnRH neurogenesis, and reduced numbers of GnRH neurons in embryonic and adult Chd7Gt/+ mice. Expression levels of GnRH1 and Otx2 in the hypothalamus and GnRHR in the pituitary are significantly reduced in adult Chd7Gt/+ mice. Additionally, Chd7 mutant embryos have CHD7 dosage dependent reductions in expression levels of Fgfr1, Bmp4, and Otx2 in the olfactory placode. Together, these data suggest that CHD7 has critical roles in the development and maintenance of GnRH neurons for regulating puberty and reproduction. Overall, our data have shown how defects in neural progenitor proliferation and neurogenesis have contributed to the Kallmann-like features associated with CHD7 deficiency.